Role of Lrrc55 in Regulation of Pancreatic β-cell Mass and Survival
Date
2021-01-22
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Abstract
During pregnancy, pancreatic β-cell mass and function are increased to accommodate for the increased maternal insulin demand. This has been tied to action of the prolactin receptor, which is present on β-cells. One gene that is differentially regulated by the prolactin receptor, and highly up regulated in islets during pregnancy, is Lrrc55. Lrrc55 is a newly described protein and an auxiliary subunit of the voltage- and calcium-activated potassium channel (BK channel). Glucolipotoxicity (GLT) is a condition commonly seen in pre-diabetic individuals that can be induced in β-cells in vitro by incubation with fatty acids and glucose. Recent work from the Huang lab found that overexpression of Lrrc55 protects β-cells from GLT-induced apoptosis. The protective effect of Lrrc55 is associated with dampening of the ER stress response and preservation of the releasable pool of calcium in the ER. Thus, I hypothesized that Lrrc55 protects β-cells from GLT-induced ER stress and apoptosis by regulating ER calcium handling. I found that Lrrc55 restored the GLT-mediated decrease in expression levels of several genes in dissociated mouse islets. These genes included the insulin regulators Pdx-1 and MafA, as well as the ER calcium regulator SERCA. Lrrc55 also attenuated the GLT-induced increase in expression of the ER calcium channel RyR. Results from activity assays indicated that Lrrc55 does not alter the activity levels of SERCA or IP3R under basal conditions. Lrrc55 also attenuated GLT-mediated increase in protein expression of pro-apoptotic molecules CHOP and IRE1α, and increased activation of the anti-apoptotic molecule Akt. Together, these results suggest a role for Lrrc55 in maintaining expression of the ER calcium regulators in the presence of GLT. Overall, this study contributes to our understanding of β-cell adaptation to stress, and the processes regulating β-cell survival.
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Lrrc55, pancreatic beta cells, β-cell survival, apoptosis, insulin, ER stress, ER calcium
Citation
Pretorius, M. (2021). Role of Lrrc55 in Regulation of Pancreatic β-cell Mass and Survival (Master's thesis, University of Calgary, Calgary, Canada). Retrieved from https://prism.ucalgary.ca.